Human patients who take morphine for the treatment of chronic pain reportedly do not develop opiate tolerance and dependence to the extent predicted. Our research suggests that one endogenous compound that affects the development of tolerance and dependence is the N-terminal metabolic fragment of substance P, SP(1-7), which interacts directly with opiate receptors or with its own specific binding site to produce changes in the development of opiate dependence or the expression of withdrawal behavior. The experiments proposed will further test the hypothesis that N-terminal metabolites of SP accumulate during chronic pain and alter the development of physical dependence and the expression of withdrawal behavior. Objective 1: We will assess the effect of SP(1-7) on the development of morphine dependence and the expression of withdrawal behavior using in vivo models of morphine dependence in the mouse. We will establish the role of SP(1-7), the N-terminal portion of SP, comparing the effects of SP(1-7) to those of compounds that inhibit [3H]SP(1-7) binding on the development of morphine dependence in mice. We will quantify changes occurring in withdrawal behavior as an indication of the degree of dependence. Objective 2: We will use two in vivo models of chronic pain, an inflammatory arthritis and a neuropathic pain model, to determine changes in opiate dependence and withdrawal occurring during chronic pain states. Objective 3: We will determine changes in the levels of SP N-terminal metabolites in brain tissue, spinal cords and blood of mice during chronic pain and morphine dependence using high-pressure liquid chromatography. Objective 4: We will continue to examine the role of SP(1-7) on morphine dependence and withdrawal by characterizing the interaction between SP(1-7) and the excitatory amino acid antagonist, MK-801. MK-801 has recently been reported to inhibit the development of morphine dependence. Experiments in our lab indicate an interaction between SP(1-7) and NMDA, an excitatory amino acid agonist.